BLR&D Research Career Scientist Award Application

项目概要/摘要： 我们小组的主要研究重点是了解胰腺癌的潜在分子机制， 和乳腺癌发病机制。我们研究的首要目标是研究细胞通路如何 (i.e.电路）失调，并可能导致不受控制的细胞生长（即癌症）。最终目标是 开发和使用小分子靶向失调的蛋白质，这些蛋白质是胰腺炎的根本原因。 和乳腺癌发病机制。 我们的实验室一直在研究一组蛋白质，称为混合谱系激酶（MLK）。的作用 MLKs在癌症中是一个新兴领域，该家族的抑制剂已通过帕金森氏症的临床试验 疾病我们已经证明MLKs的抑制剂可以重新用于治疗三阴性乳腺癌（TNBC）。 和胰腺导管腺癌（PDAC）。 我们最近的研究结果（通过VA-Merit资助）表明，MLK家族成员之一MLK 3高度表达， 在人胰腺癌肿瘤中过表达，并且是细胞生长所必需的。此外，使用动物 在胰腺癌模型中，我们观察到MLKs抑制剂改善了PDAC并且动物存活 与媒介物处理的动物相比长得多。我们计划进一步探索MLK 3失调如何促进 胰腺癌并最终使用抑制剂进行治疗干预。 另外两个项目（由国家癌症研究所/国家卫生研究院的两笔赠款供资）是关于乳腺癌的。我们早些时候报道说， 雌激素对MLK 3活性抑制是ER+乳腺癌细胞存活和生长所必需的。我们 还观察到另一种受体HER 2也能够抑制HER 2+乳腺癌中MLK 3的活性 这也是他们生存的必要条件。综上所述，这些令人兴奋的结果表明， MLK 3通过ER和HER 2的表达为乳腺癌细胞的生长和增殖提供了存活信号。因此，我们认为， 我们开发了一种新的纳米颗粒，负载MLK 3激活剂，神经酰胺（一种脂质），能够诱导 在HER 2+和ER+乳腺癌细胞中显著的细胞死亡。在ER+和HER 2+乳腺癌的动物模型中， 神经酰胺-纳米颗粒能够降低肿瘤负荷。此外，我们还观察到，在人类TNBC中， 在乳腺癌肿瘤中，MLK 3的活性与ER+乳腺癌肿瘤相比非常高。通过机理研究， 我们确定MLK 3活性在TNBC中起着矛盾的存活作用。基于我们的细胞和人类 根据肿瘤数据，用MLK抑制剂治疗移植有TNBC肿瘤（即PDX）的动物，实际上， 肿瘤负荷降低，动物寿命延长。我们的研究结果首先证明， MLK 3/MLKs抑制剂可以显著降低TNBC肿瘤负荷，并可以延长动物的寿命。同样地， 根据我们的细胞和人类肿瘤数据，赫赛汀（即抗HER 2+治疗）耐药的肿瘤负荷 动物中的人肿瘤（即PDX）减少。 综上所述，我们的研究结果最终表明MLK 3/MLKs的激活剂可用于治疗ER+和 HER 2+乳腺癌，而MLK 3/MLKs的抑制剂可以作为TNBC的治疗干预 和胰腺导管腺癌（PDAC）。我们的综合研究还表明， 在使用任何靶向药物之前，了解疾病的潜在分子机制是重要的。 疗法

Project Summary/Abstract: The main focus of research in our group is to understand the underlying molecular mechanisms of pancreatic and breast cancer pathogenesis. The overarching goal of our research is to investigate how the cellular pathways (i.e. circuits) are dysregulated and can lead to uncontrolled cell growth (i.e. cancer). The ultimate goal is to develop and use small molecules to target the dysregulated proteins that are the underlying cause of pancreatic and breast cancers pathogenesis. Our laboratory has been working with a group of proteins, called Mixed Lineage Kinases (MLKs). The roles of MLKs in cancer is an emerging area and the inhibitor of this family has gone through clinical trial for Parkinson's Disease. We have shown that inhibitor of MLKs can be repurposed to treat Triple Negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC). Our recent results (funded through VA-Merit) demonstrate that one of the MLK family member, MLK3 was highly overexpressed in human pancreatic cancer tumors and was necessary for cell growth. Furthermore, using animal models of pancreatic cancer, we have observed that MLKs inhibitor ameliorate PDAC and the animals survive much longer, compared to vehicle treated animals. We plan to further explore how MLK3 dysregulation promotes pancreatic cancer and ultimately use the inhibitors for therapeutic intervention. The other two projects (funded through 2 NCI/NIH grants) are on breast cancer. We reported earlier that suppression of MLK3 activity by Estrogen was necessary for ER+ breast cancer cell survival and growth. We also observed that the other receptor, HER2 was also able to suppress MLK3 activity in HER2+ breast cancer and this was also necessary for their survival. Taken together, these exciting results suggest that suppression of MLK3 by ER and HER2 provides survival signals for breast cancer cell growth and proliferation. Therefore, we developed a novel nanoparticle, loaded with MLK3 activator, ceramide (a lipid) that was able to induce significant cell death in HER2+ and ER+ breast cancer cells. In animal models of ER+ and HER2+ breast cancer, the ceramide-nanoparticle was able to reduce tumor burden. In addition, we also observed that in human TNBC tumors, the activity of MLK3 was very high compared to ER+ breast cancer tumors. Through mechanistic studies, we identified that MLK3 activity plays paradoxically a survival role in TNBC. Based on our cellular and human tumor data, the animal transplanted with TNBC tumors (i.e. PDXs) were treated with MLKs inhibitors, indeed the tumor burden was reduced and the animal life was prolonged. Our results are first in line to demonstrate that MLK3/MLKs inhibitors can significantly reduce TNBC tumor burden and can prolog animals' life. Similarly, following our cellular and human tumor data, the tumor burden of Herceptin (i.e. anti-HER2+ therapy) resistant human tumors in animal (i.e. PDXs) was reduced. Taken together, our results suggest conclusively that activator of MLK3/MLKs could be used to treat ER+ and HER2+ breast cancer, whereas the inhibitor of MLK3/MLKs could serve as a therapeutic intervention for TNBC and pancreatic ductal adenocarcinoma (PDAC). Our comprehensive studies also suggest that it is utmost important to understand the detail underlying molecular mechanisms of a disease before using any targeted therapy.